Chemical communication in the nervous system is tightly regulated by the flux of calcium ions through certain subtypes of voltage-gated channels. A decrease in calcium flux at synapses can cause neurological diseases. For example, Lambert-Eaton Myasthenic Syndrome (LEMS) is a neurological autoimmune disorder of the neuromuscular junction characterized by debilitating muscle weakness. While LEMS is often a paraneoplastic syndrome associated with small cell lung cancer, it can also be idiopathic. This muscle weakness has been shown to be due to an auto-antibody-mediated removal of a fraction of presynaptic P/Q-type (Cav2.1) calcium channels, which are known to be involved with transmitter release at the mammalian neuromuscular junction, and a partial compensatory up-regulation of N-type (Cav2.2), L-type (Cav1), and R-type (Cav2.3) channels. N-type and P/Q-type channels appear to be the most relevant for the control of transmitter release as they selectively bind directly to and co-localize with transmitter release sites. Despite a compensatory expression of other calcium channel types, the overall effect is a decrease in the quantal content of transmitter release from the NMJ. LEMS results in muscle weakness and is associated with compromised motor function. This disease is estimated to affect 1:100,000 individuals in the United States; however, the true incidence of LEMS remains unknown as it is often undiagnosed in patients.
Current treatment strategies are very limited, and those available are indirect and sometimes associated with undesirable side effects. If cancer is present, anti-tumor therapy is the priority. In any case, this type of neuromuscular weakness can be treated using either immunosuppressants or symptomatic treatment approaches. Immunosuppressants have not been favored, as side-effects may be severe and include leukopenia, liver dysfunction, nausea, vomiting, and hair loss. The most common therapeutic approach is the use of the potassium channel blocker 3,4-diaminopyridine (DAP), which indirectly increases presynaptic Ca2+ entry by broadening the action potential waveform, leading to an increase in transmitter release. In clinical trials, 10-20 mg of the potassium channel blocker 3,4-diaminopyridine (DAP), which increases calcium entry by broadening the action potential depolarization, was given 3 times per day, and led to serum levels of about 0.5 μM. However, DAP is only partially effective in LEMS. Although generally well-tolerated, DAP can have dose-limiting side-effects that include paresthesia, gastric symptoms, difficulty in sleeping, fatigue, and deterioration of muscle. The latter two may be due to reported effects on axonal K+ channels that limit firing frequencies and/or reduction in activity-dependent facilitation caused by DAP. Thus, the current LEMS treatment approach indirectly increases calcium entry into the nerve terminal, but there are currently no other common treatment options.
Another disorder in which calcium channel agonists may be useful is myasthenia gravis. Myasthenia gravis is an autoimmune disorder characterized by blockade or loss of acetylcholine receptors at the neuromuscular junction. The symptoms of this disorder are often managed using acetylcholinesterase blockers.
Selective calcium channel agonists which increase the ion flux through N- and P/Q-type calcium channels represent attractive potential therapeutics for LEMS and other neuromuscular diseases; however, to date, no such agonists have been identified.